Specific individualised lifestyle advice on a cardioprotective dietary pattern, physical activity and smoking cessation. This lifestyle advice should be given by the primary health care team for three to six months prior to initiating drug treatment

Drug therapy indicated for people with extreme risk factor levels.**

Cardiovascular risk assessments every one to five years, depending on clinical circumstances.

less than 10% (Primary prevention)

General lifestyle advice on a cardioprotective dietary pattern, physical activity and smoking cessation

Non-pharmacological approach to treating multiple risk factors

Lifestyle advice aimed at reducing cardiovascular risk

Further cardiovascular risk assessment in five years.

*People who have had a previous cardiovascular event (angina, MI, angioplasty, coronary artery bypass grafts, TIA, ischaemic stroke or peripheral vascular disease) OR people with certain genetic lipid disorders OR people with diabetes mellitus and who are over 40 years.

**People with isolated high risk-factor levels either TC >8 mmol/l or BP ≥160/100 mm Hg should have these risk factors treated and considered for drug therapy to reduce levels of other modifiable factors and, therefore, global risk.

Annex 2

Cost effectiveness of statin therapy

In Scotland in the year to 31 March 2006 expenditure on statins was £70 million, equivalent to 7.2% of the drugs budget. Five statins, atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin currently have a UK marketing authorisation for a range of licensed indications from primary prevention as an adjunct to dietary control, to secondary prevention in people with manifest cardiovascular disease and for patients with primary or familial hypercholesterolaemia. For a list of licensed indications by individual statin, see the latest edition of the British National Formulary.131

No analysis of expenditure by licensed indication is available but the major patient groups currently prescribed statins are those identified as being:

patients with established cardiovascular disease (CVD) or familial hypercholesterolaemia or

asymptomatic patients with serum total cholesterol of =5.0 mmol/l and a 10 year risk of a major coronary event of =30%, who do not respond adequately to diet and other lifestyle advice.

The clinical and cost effectiveness for the use of statins in patients with existing CHD and familial hypercholesterolaemia is well established.199 There is considerable uncertainty about their cost effectiveness in primary prevention. This is particularly important given other guideline groups have recommended expanding the treatment groups for statins. For example, JBS228 proposed widening the patient groups to be prescribed statins (in conjunction with lifestyle interventions and appropriate use of antihypertensive drugs) to:

asymptomatic individuals with a CVD risk of ≥20% over ten years; or

those with an elevated systolic blood pressure of ≥160mm Hg or diastolic blood pressure =100 mm Hg; or

individuals with a total cholesterol to HDL ratio of ≥6.0

The JBS2 guidelines also proposed a total cholesterol treatment target of <4.0 mmol/l or a 25% reduction in total cholesterol (LDL cholesterol <2.0 mmol/l or a 50% reduction), whichever gets the person to the lowest absolute value.

Such recommendations raise several important economic issues, particularly around measuring the incremental costs and benefits of population based campaigns. For example, the clinical evidence for a public health campaign to titrate asymptomatic individuals aggressively to low cholesterol targets is not currently available, and is unlikely to be made available from clinical trials. Thus whilst RCTs may show the benefit of using a high dose statin compared to placebo ortoalowdoseinadefinedpopulation,theresultsmaynotgeneraliseto aprimaryprevention population. There may also be other effects associated with giving drugs to individuals at risk of CVD that are difficult to capture as end points in clinical trials, particularly around compliance rates and patient preferences and attitudes.

Cost effectiveness evidence

A literature search was undertaken that identified nine UK studies that were methodologically sound and presented cost effectiveness analyses. Five of these were reported in the Technology

Assessment Report from researchers based at Sheffield University, the sixth was that report, itself.199 The remaining three studies306-308were published following the publication of the Technology Assessment Report.

Five of the studies were of the use of statins in primary prevention,308-312two were health technology assessments that modelled use in primary and secondary prevention199,309 and two were secondary prevention only.306,307 Four of the five primary prevention studies were based on the WOSCOPS trial.191 The other study modelled the cost effectiveness of the five licensed statins for primary prevention.308 The secondary prevention studies used data from the Heart Protection Study of 20,536 high risk individuals194 and the two health technology assessments pooled clinical data from several trials.

All but three of the studies199,307,308 were completed prior to the introduction of simvastatin as a generic product - at a price (as at November 2006) of £55 a year for simvastatin 40 mg, compared to £367 a year for the proprietary product of atorvastatin 40 mg. Therefore, the results from the earlier studies overstate the cost per life year gained, or cost per quality adjusted life year, for the options that can be delivered using generic simvastatin.

Asymptomatic individuals without established CHD or CVD

The systematic literature review concluded that for asymptomatic individuals, at low levels of risk of CHD, the cost per life year gained from prescribing statins compared to placebo, varied between £20,000 and £30,000.199 The economic modelling of people with a ≥30% ten year risk of CHD (approximating to a ≥40% ten year CVD risk) reported a wider range, varying from £9,500 to £36,800 per quality adjusted life year (QALY) in men aged 45 and 85 and £13,700 to £47,400 per QALY for women of the same ages.

Adopting CVD risk levels of 20% over ten years reduced the modelled costs per QALY to £6,800 to £27,600 for men aged 45 and 85 years, with women having similar or slightly lower values.

The CVD analyses have lower incremental cost effectiveness ratios, that is are more cost effective, than the CHD analyses. This is presumably because of the higher costs to manage strokes initially and in subsequent years, compared to CHD diagnoses. This difference is particular notable in the older age groups where the costs per QALY for CVD risks are below £30,000 per QALY in all age groups.

One study looked at treating asymptomatic men with raised baseline cholesterol of 7.5 mmol/l and varying risk factors and found such treatment to be cost effective at all risk levels.311

The study comparing the cost effectiveness of the five statins4 assumed a mean initial baseline total cholesterol of 6.4 mmol/l and applied the efficacy rates observed in trials for each statin to derive a range of treated cholesterol values. These were used, in conjunction with Framingham risk equations, to predict the CHD events saved as a result of the cholesterol reductions. The results from this study may not generalise to Scotland where the baseline total cholesterol for untreated individuals, as observed in the Scottish Heart Survey 2003 was 6.0 mmol/l.

Individuals with established CHD or CVD

The systematic literature review noted the cost per life year gained was lower in secondary prevention of CHD compared to primary prevention because people were at higher risk of events.199

This report also modelled the cost effectiveness of adopting a risk measure based on CVD. The resultant costs per QALY were lower than for established CHD, ranging from £9,000 to £13,100 for men between 45 to 85 years of age and slightly lower for women in the same age range being £8,400 to £11,700.

The cost effectiveness of treating those with established CVD was also demonstrated in the economic evaluations that accompanied the Heart Protection Study.306,307 The first study compared the hospitalisation costs and cost of simvastatin 40 mg for 20,536 individuals with established disease over the five year period of the trial.306 The second study extrapolated the trial data to evaluate the lifetime benefits for people in different ages and with different risks of CVD.307

Prescribing generic simvastatin 40 mg/day was cost saving for most risk and age categories, with the reduced costs from fewer hospital admissions outweighing the drug costs. In people aged from 70 years with a relatively low disease risk, (24% over ten years) the cost per life year gained was under £100.

The economic evaluation also modelled data for younger people and lower risk thresholds than observed in the trial. The results showed that prescribing simvastatin 40 mg/day was cost effective compared to placebo for risk thresholds as low as 10% over ten years and for all age groups.

Weaknesses of the models

All of the economic models assume that identifying patients at the various risk thresholds is costless and that the assessment tool is 100% accurate. None include the cost of adverse events. The absence of such costs could overstate cost effectiveness but such an effect is likely to be much smaller than the savings from using generic statins.

In summary, the published evidence supports prescribing statins to people with established CVD and for individuals with a CVD risk as low as 10% over ten years or with baseline cholesterol levels of over 7.5 mmol/l. No evidence was identified on the cost effectiveness of treating individuals to a total cholesterol target of less than 5 mmol/l or those with the single risk factor of raised blood pressure.

No systematic literature reviews were identified which looked at the relative cost effectiveness of such programmes. Two of the studies found in the literature search undertaken for the statins analyses provide some comparative data. One study found that the cost effectiveness of statins was poorer than for other treatments.313 The gross discounted cost per life gained was: £55 for aspirin post-myocardial infarction, £45 for bendroflumethazide treatment for elderly people with hypertension, £1,510 for low cost mixed drug antihypertensive regimens for middle-aged people, £230 for beta-blockers post-myocardial infarction and £290 for the Mediterranean diet post-myocardial infarction. In comparison, statins had a cost per life year gained of between £5,400 and £13,300 for primary prevention of CHD and £3,800 to £9,300 for secondary prevention.

A similar study of prevention programmes in Spain ranked interventions by cost per life year gained.314 The ordering, beginning with the most cost effective was: smoking cessation, hypertension, dietary treatment and drug treatment for hypercholesterolaemia. The statins treatment arm had a cost per life year gained of three times that of the dietary programme.

The objective of such comparisons is to improve decision- making on the allocation of scarce resources for competing therapies to prevent and manage CVD. This is not straightforward and best practice315 suggests such decisions should also consider:

that the financial costs involved in treating all groups who could potentially benefit from lipid lowering are large. NHS resources are finite and therefore prioritisation is necessary. This should be based on evidence-based estimation of capacity to benefit

the cost effectiveness of lipid lowering interventions rises as the absolute cardiovascular risk increases. The risk level at which treatment is given needs to be influenced by both cost effectiveness and overall cost, as determined by the price of statins. If more statins were available as generic products, more people who would benefit could be treated for the same resources

there are interventions in the prevention of CVD (eg lifestyle changes) which are considerably more cost effective than statins and these should already be in place before lipid lowering is initiated. However, for the higher risk groups, cost effectiveness of statins is on a par with many other interventions of proven effectiveness in other disease areas provided by the NHS.

2. Obtaining a pre-treatment, baseline CK level may be considered in patients who are at high risk of experiencing a muscle toxicity (eg, older individuals or when combining a statin with an agent known to increase myotoxicity), but this is not routinely necessary in other patients.

3. It is not necessary to measure CK levels in asymptomatic patients during the course of statin therapy, because marked, clinically important CK elevations are rare and are usually related to physical exertion or other causes.

4. Patients receiving statin therapy should be counselled about the increased risk of muscle complaints, particularly if the initiation of vigorous, sustained endurance exercise or a surgical operation is being contemplated; they should be advised to report such muscle symptoms to a health professional.

5. CK measurements should be obtained in symptomatic patients to help gauge the severity of muscle damage and facilitate a decision of whether to continue therapy or alter doses.

6. In patients who develop intolerable muscle symptoms with or without a CK elevation and in whom other aetiologies have been ruled out, the statin should be discontinued. Once asymptomatic, the same or different statin at the same or lower dose can be restarted to test the reproducibility of symptoms. Recurrence of symptoms with multiple statins and doses requires initiation of other lipid-altering therapy.

7. In patients who develop tolerable muscle complaints or are asymptomatic with a CK <10 x the upper limit of normal, statin therapy may be continued at the same or reduced doses and symptoms may be used as the clinical guide to stop or continue therapy.

8. In patients who develop rhabdomyolysis (a CK >10,000 IU/L or a CK >10 times the upper limit of normal with an elevation in serum creatinine or requiring IV hydration therapy), statin therapy should be stopped. IV hydration therapy in a hospital setting should be instituted if indicated for patients experiencing rhabdomyolysis. Once recovered, the risk vs benefit of statin therapy should be carefully reconsidered.

Annex 4

Recommendations to healthcare professionals regarding the liver and statin safety

1. During the routine general evaluation of patients being considered for statin and other lipid-lowering therapy, it is advisable to obtain liver transaminase levels. If these tests are found to be abnormal, further investigation should be performed to determine the aetiology of the abnormal test results.

2. Until there is a change in the FDA-approved prescribing information for statins, it is appropriate to continue to measure transaminase levels before starting therapy, 12 weeks after initiating therapy, after a dose increase, and periodically thereafter. However, routine monitoring of liver function tests is not supported by the available evidence and the current recommendation for monitoring needs to be reconsidered by the FDA.

3. The clinician should be alert to patient reports of jaundice, malaise, fatigue, lethargy, and related symptoms in patients taking statin therapy as a signal of potential hepatotoxicity. Evidence for hepatotoxicity includes jaundice, hepatomegaly, increased bilirubin level and elevated prothrombin time (rather than simple elevations in liver transaminase levels).

4. The preferred biochemical test to ascertain significant liver injury is bilirubin, which, in the absence of biliary obstruction, is a more accurate prognosticator of liver injury than isolated aminotransferase levels.

5. Should the clinician identify objective evidence of significant liver injury in a patient receiving a statin, the statin should be discontinued. The aetiology should be sought and, if indicated, the patient referred to a gastroenterologist or hepatologist.

6. If an isolated asymptomatic transaminase level is found to be elevated 1-3 times the upper limit of normal, there is no need to discontinue the statin.

7. If an isolated asymptomatic transaminase level is found to be 3 times the upper limit of normal during a routine evaluation of a patient administering a statin, the test should be repeated and, if still elevated, other aetiologies should be ruled out. Consideration should be given to continuing the statin, reducing its dose, or discontinuing it based on clinical judgment.

Annex 5

Recommendations to healthcare professionals regarding the kidney and statin safety

1. During the management of patients with statin therapy, it is not necessary to carry out serum creatinine and proteinuria monitoring routinely for the purpose of identifying an adverse effect, although an assessment of renal function is advisable before initiating statin therapy.

2. If serum creatinine becomes elevated in a patient without rhabdomyolysis while receiving statin therapy, there is generally no need to withdraw the statin but in some cases, according to prescribing information, an adjustment in the statin dose may be required.

3. If unexpected proteinuria develops in a patient receiving a statin, there is no need to withdraw statin therapy or to alter the dose of the statin. An investigation into the cause of the proteinuria is warranted, as is consideration of a change in the statin dose as guided by the prescribing information for each statin.

4. Chronic kidney disease does not preclude the use of a statin. However, the dose of some statins should be adjusted in cases of moderate or severe renal insufficiency.

3. If another aetiology of the neurological symptoms is not identified, it is appropriate to withdraw statin therapy for a period of 3-6 months to establish whether an apparent association with statin therapy exists.

4. If the patient's neurological symptoms improve while off statin therapy, a presumptive diagnosis of statin-induced peripheral neuropathy might be made. However, because of the proven benefit of statin therapy, reinitiation of statin therapy should be considered with a different statin and dose.

5. If the patient's neurological symptoms do not improve after statin therapy has been withdrawn for the specified period, statin therapy should be restarted based on a risk- benefit analysis.

6. If the patient experiences impaired cognition while receiving statin therapy it is appropriate to follow a similar course of evaluation as suggested above for peripheral neuropathy, ie, first rule out other aetiologies, and if none are found, then withdraw the statin for 1-3 months. If improvement is not seen, statin therapy should be restarted based on a risk- benefit analysis.